Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disease characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells, which has become the fourth leading cause of end-stage renal diseases. Currently, treatment options for ADPKD remain limited. The purpose of this study was to discover an effective therapeutic drug for ADPKD. With virtual screening, Madin-Darby canine kidney (MDCK) cyst model, embryonic kidney cyst model and kidney-specific Pkd1 knockout mouse (PKD) model, we identified obacunone as a candidate compound for ADPKD drug discovery from a natural antioxidant compound library. In vitro experiments showed that obacunone significantly inhibited cyst formation and expansion of MDCK cysts and embryonic kidney cysts in a dose-dependent manner. In vivo, obacunone treatment significantly reduced the renal cyst development in PKD mice. Western blot and morphological analysis revealed that obacunone served as a NRF2 activator in ADPKD, which suppressed lipid peroxidation by up-regulating GPX4 and finally restrained excessive cell proliferation by down-regulating mTOR and MAPK signaling pathways. Experimental data demonstrated obacunone as an effective renal cyst inhibitor for ADPKD, indicating that obacunone might be developed into a therapeutic drug for ADPKD treatment.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is a human inherited disease with an estimated prevalence of between one in 2500 to one in 1000 individuals [1]
E13.5 embryonic kidneys cultured in transwell form cysts with 100 μM 8-Br-cAMP stimulation, which is used as an ex vivo model of ADPKD
We found that GPX4 was down-regulated as the decline of NRF2 activity in Pkd1 knockout mouse (PKD) kidneys, implying that GPX4 is involved in the progress of ADPKD
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is a human inherited disease with an estimated prevalence of between one in 2500 to one in 1000 individuals [1]. It is characterized by progressive enlargement of fluid-filled cysts derived from renal tubular epithelial cells. With the progress of ADPKD, it eventually evolves into end-stage renal disease (ESRD), which seriously endangers the lives of patients [4,5]. Patients with ESRD have to undergo replacement therapy [7]. These facts have brought a huge economic burden to patients and society [8]
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